Research for the last few years in our laboratory has revealed that one of the physiological functions of APP is to regulate cellular functions and survival. In particular, APP has been found to be a trophic molecule that regulates neurite extension in vitro and synaptic formation/structure in vivo. Considering that in many instances trophic factors protect neurons from damages caused by various injuries, APP is a prominent candidate for the intervention of neuronal injuries. Therefore, we propose to study the involvement of APP in several models of neuronal and synaptic degeneration and regeneration. In Specific Aim 1, we will determine the degree of APP involvement in the rabbit spinal cord ischemia model (RSCIM). Our hypothesis is that APP synthesis and degradation are affected by ischemia as a part of the protective mechanisms to counteract the damage induced by ischemia. APP isoforms before and after ischemia will be quantified and localized, where possible, at both protein and mRNA levels using various techniques including Western blotting, immunohistochemistry, Northern blotting, slot blotting, RT-PCR technique, and in situ hybridization. This work serves as a foundation for Specific Aim 2 where we will optimize the procedure for the APP-peptide therapy using RSCIM. This study is based on our recent finding that a short peptide fragment representing the active trophic domain of APP antagonizes the ischemia-induced damage in rabbit spinal cords. We will evaluate ischemic injury using clinical, biochemical, molecular biological, and morphological criteria. Morphological criteria include neuronal and synaptic counts. In Specific Aim 3, we will examine a potential APP involvement in the sprouting reactions in the molecular layer of the dentate gyrus after the perforant path (PP) lesion. We will ask which neurons produce APP in response to PP lesion, and also if the infusion of a peptide which interferes with the function of APP inhibits the sprouting. Specific Aim 4 will test the hypothesis that the effect of NGF and beta-FGF to rescue medioseptal neurons from degeneration after the transection of fimbria-fornix (FF) is partially through the activation of putative APP pathways. We will investigate the effect of APP peptide infusion on the medioseptal neurons after FF lesion. Then, we will attempt to antagonize the effects of NGF and bFGF by co-infusing a peptide that completes with APP and blocks its function. Finally, in Specific Aim 5, we will test the potential effect of APP agonists and antagonists in the protection by growth factors from glutamate-induced neuronal toxicity employing the in vitro culture model.